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Magnesium is an essential element in biological systems. Magnesium occurs typically as the Mg2+ ion. It is an essential mineral nutrient for life and is present in every cell type in every organism. For example, ATP (adenosine triphosphate), the main source of energy in cells, must be bound to a magnesium ion in order to be biologically active. What is called ATP is often actually Mg-ATP. . Similarly, magnesium plays a role in the stability of all polyphosphate compounds in the cells, including those associated with DNA and RNA synthesis.
A balance of magnesium is vital to the well being of all organisms. Magnesium is a relatively abundant ion in the lithosphere and is highly bioavailable in the hydrosphere. This ready availability, in combination with a useful and very unusual chemistry, may have led to its usefulness in evolution as an ion for signalling, enzyme activation and catalysis. However, the unusual nature of ionic magnesium has also led to a major challenge in the use of the ion in biological systems. Biological membranes are impermeable to Mg2+ (and other ions) so transport proteins must facilitate the flow of Mg2+, both into and out of cells and intracellular compartments.
Biological range, distribution, and regulation
In animals it has been shown that different cell types maintain different concentrations of magnesium. It seems likely that the same is true for plants. This suggests that different cell types may regulate influx and efflux of magnesium in different ways based on their unique metabolic needs. Interstitial and systemic concentrations of free magnesium must be delicately maintained by the combined processes of buffering (binding of ions to proteins and other molecules) and muffling (the transport of ions to storage or extracellular spaces).
Recently in animals, magnesium has been recognized as an important signaling ion, both activating and mediating many biochemical reactions.
The importance of magnesium to proper cellular function cannot be overstated. Deficiency of the nutrient results in disease in the affected organism. In single-celled organisms such as bacteria and yeast, low levels of magnesium manifests in greatly reduced growth rates. In magnesium transport knockout strains of bacteria, healthy rates are maintained only with exposure to very high external concentrations of the ion. In yeast, mitochondrial magnesium deficiency is also leads to disease.
In animals, magnesium deficiency (hypomagnesemia) is seen when the environmental availability of magnesium is low. In ruminant animals, particularly vulnerable to magnesium availability in pasture grasses, the condition is known as ‘grass tetany’. Hypomagnesemia is identified by a loss of balance due to muscle weakness. A number of genetically attributable hypomagnesemia disorders have also been identified in humans.
Overexposure to magnesium may be toxic to individual cells, though these effects have been difficult to show experimentally. In humans the condition is termed hypermagnesemia, and is well documented, though it is usually caused by loss of kidney function. In healthy individuals, excess magnesium is rapidly excreted in the urine (Harrison’s Principles of Internal Medicine, Online Edition).
- Main article: Magnesium deficiency (medicine)
Magnesium deficiency in humans was first described in the medical literature in 1934. The adult human daily nutritional requirement, which is affected by various factors including gender, weight and size, is 300-400 mg/day. Inadequate magnesium intake frequently causes muscle spasms, and has been associated with cardiovascular disease, diabetes, high blood pressure, anxiety disorders, migraines, osteoporosis and cerebral infarction. Acute deficiency (see hypomagnesemia) is rare, and is more common as a drug side effect (such as chronic alcohol or diuretic use) than from low food intake per se, but it can also occur within people fed intravenously for extended periods of time. The incidence of chronic deficiency resulting in less than optimal health is debated.
The DRI upper tolerated limit for supplemental magnesium is 350 mg/day (calculated as milligrams (mg) of elemental magnesium in the salt). (Supplements based on amino acid chelates, such as glycinate, lysinate etc., are much better tolerated by the digestive system and do not have the side effects of the older compounds used, while sustained release supplements prevent the occurrence of diarrhea.)[How to reference and link to summary or text] The most common symptom of excess oral magnesium intake is diarrhea. Since the kidneys of adult humans excrete excess magnesium efficiently, oral magnesium poisoning in adults with normal renal function is very rare. Infants, which have less ability to excrete excess magnesium even when healthy, should not be given magnesium supplements, except under a physician's care.
Magnesium salts (usually in the form of magnesium sulfate or chloride when given parenterally) are used therapeutically for a number of medical conditions, see Epsom salts for a list of conditions which have been treated with supplemental magnesium ion. Magnesium is absorbed with reasonable efficiency (30% to 40%) by the body from any soluble magnesium salt, such as the chloride or citrate. Magnesium is similarly absorbed from Epsom salts, although the sulfate in these salts adds to their laxative effect at higher doses. Magnesium absorption from the insoluble oxide and hydroxide salts (milk of magnesia) is erratic and of poorer efficiency, since it depends on the neutralization and solution of the salt by the acid of the stomach, which may not be (and usually is not) complete.
Magnesium orotate may be used as adjuvant therapy in patients on optimal treatment for severe congestive heart failure, increasing survival rate and improving clinical symptoms and patient's quality of life.
Magnesium can affect muscle relaxation through direct action on the cell membrane. Mg++ ions close certain types of calcium channels, which conduct a positively charged calcium ion into the neuron. With an excess of magnesium, more channels will be blocked and the nerve will have less activity.[How to reference and link to summary or text]
Magnesium-containing Epsom salts are especially used in treating the hypertension of eclampsia. Even if the case is not eclampsia, there may be antihypertensive effects of having a substantial portion of the intake of sodium chloride (NaCl) exchanged for e.g. magnesium chloride; NaCl is an osmolite and increases arginine vasopressin (AVP) release, which increases extracellular volume and thus results in increased blood pressure. However, not all osmolites have this effect on AVP release, so with magnesium chloride, the increase in osmolarity may not cause such a hypertensive response.
Green vegetables such as spinach provide magnesium because of the abundance of chlorophyll molecules which contain the ion. Nuts (especially cashews and almonds), seeds, and some whole grains are also good sources of magnesium.
Although many foods contain magnesium, it is usually found in low levels. As with most nutrients, daily needs for magnesium are unlikely to be met by one serving of any single food. Eating a wide variety of fruits, vegetables, and grains will help ensure adequate intake of magnesium.
Because magnesium readily dissolves in water, refined foods, which are often processed or cooked in water and dried, are generally poor sources of the nutrient. For example, whole-wheat bread has twice as much magnesium as white bread because the magnesium-rich germ and bran are removed when white flour is processed. The table of food sources of magnesium suggests many dietary sources of magnesium.
Hard" water can also provide magnesium, but "soft" water does not contain the ion. Dietary surveys do not assess magnesium intake from water, which may lead to underestimating total magnesium intake and its variability.
Too much magnesium may make it difficult for the body to absorb calcium. Not enough magnesium can lead to hypomagnesemia as described above, with irregular heartbeats, high blood pressure (a sign in humans but not some experimental animals such as rodents), insomnia and muscle spasms (fasciculation). However, as noted, symptoms of low magnesium from pure dietary deficiency are thought to be rarely encountered.
Following are some foods and the amount of magnesium in them:
- spinach (1/2 cup) = 80 milligrams (mg)
- peanut butter (2 tablespoons) = 50 mg
- black-eyed peas (1/2 cup) = 45 mg
- milk: low fat (1 cup) = 40 mg
Mg2+ is the fourth most abundant metal ion in cells (in moles) and the most abundant free divalent cation — as a result it is deeply and intrinsically woven into cellular metabolism. Indeed, Mg2+-dependent enzymes appear in virtually every metabolic pathway: specific binding of Mg2+ to biological membranes is frequently observed, Mg2+ is also used as a signalling molecule, and much of nucleic acid biochemistry requires Mg2+, including all reactions which require release of energy from ATP. In nucleotides, the triple phosphate moiety of the compound is invariably stabilized by association with Mg2+ in all enzymic processes.
The chemistry of the Mg2+ ion, as applied to enzymes, uses the full range of this ion’s unusual reaction chemistry to fulfill a range of functions. Mg2+ interacts with substrates, enzymes and occasionally both (Mg2+ may form part of the active site). Mg2+ generally interacts with substrates through inner sphere coordination, stabilising anions or reactive intermediates, also including binding to ATP and activating the molecule to nucleophilic attack. When interacting with enzymes and other proteins Mg2+ may bind using inner or outer sphere coordination, to either alter the conformation of the enzyme or take part in the chemistry of the catalytic reaction. In either case, because Mg2+ is only rarely fully dehydrated during ligand binding, it may be a water molecule associated with the Mg2+ that is important rather than the ion itself. The Lewis acidity of Mg2+ (pKa 11.4) is used to allow both hydrolysis and condensation reactions (most commonly phosphate ester hydrolysis and phosphoryl transfer) that would otherwise require pH values greatly removed from physiological values.
Essential role in the biological activity of ATP
Nucleic acids have an important range of interactions with Mg2+. The binding of Mg2+ to DNA and RNA stabilises structure; this can be observed in the increased melting temperature (Tm) of double-stranded DNA in the presence of Mg2+. Additionally, ribosomes contain large amounts of Mg2+ and the stabilisation provided is essential to the complexation of this ribo-protein. A large number of enzymes involved in the biochemistry of nucleic acids bind Mg2+ for activity, using the ion for both activation and catalysis. Finally, the autocatalysis of many ribozymes (enzymes containing only RNA) is Mg2+ dependent (e.g. the yeast mitochondrial group II self splicing introns).
Magnesium ions can be critical in maintaining the positional integrity of closely clustered phosphate groups. These clusters appear in numerous and distinct parts of the cell nucleus and cytoplasm. For instance hexahydrated Mg2+ ions bind in the deep major groove and at the outer mouth of A-form nucleic acid duplexes.
Cell membranes and walls
Biological cell membranes and cell walls are polyanionic surfaces. This has important implications for the transport of ions, particularly because it has been shown that different membranes preferentially bind different ions. Both Mg2+ and Ca2+ regularly stabilise membranes by the cross-linking of carboxylated and phosphorylated head groups of lipids. However, the envelope membrane of E. coli has also been shown to bind Na+, K+, Mn2+ and Fe3+. The transport of ions is dependent on both the concentration gradient of the ion and the electric potential (ΔΨ) across the membrane, which will be affected by the charge on the membrane surface. For example, the specific binding of Mg2+ to the chloroplast envelope has been implicated in a loss of photosynthetic efficiency by the blockage of K+ uptake and the subsequent acidification of the chloroplast stroma.
The Mg2+ ion tends to bind only weakly to proteins (Ka ≤ 105) and this can be exploited by the cell to switch enzymatic activity on and off by changes in the local concentration of Mg2+. Although the concentration of free cytoplasmic Mg2+ is on the order of 1 mmol/L, the total Mg2+ content of animal cells is 30 mmol/L and in plants the content of leaf endodermal cells has been measured at values as high as 100 mmol/L (Stelzer et al., 1990), much of which is buffered in storage compartments. The cytoplasmic concentration of free Mg2+ is buffered by binding to chelators (e.g. ATP), but also more importantly by storage of Mg2+ in intracellular compartments. The transport of Mg2+ between intracellular compartments may be a major part of regulating enzyme activity. The interaction of Mg2+ with proteins must also be considered for the transport of the ion across biological membranes.
In biological systems, only manganese (Mn2+) is readily capable of replacing Mg2+, and only in a limited set of circumstances. Mn2+ is very similar to Mg2+ in terms of its chemical properties, including inner and outer shell complexation. Mn2+ effectively binds ATP and allows hydrolysis of the energy molecule by most ATPases. Mn2+ can also replace Mg2+ as the activating ion for a number of Mg2+-dependent enzymes, although some enzyme activity is usually lost. Sometimes such enzyme metal preferences vary among closely related species: for example is that the reverse transcriptase enzyme of lentiviruses like HIV, SIV and FIV is typically dependent on Mg2+, whereas the analogous enzyme for other retroviruses prefers Mn2+.
Importance in drug binding
An article investigating the structural basis of interactions between clinically reelevant antibiotics and the 50S ribosome appeared in Nature in October 2001. High resolution x-ray crystallography established that these antibiotics only associate with the 23S rRNA of a ribosomal subunit, and no interactions are formed with a subunit's protein portion. The article stresses that the results show "the importance of putative Mg2+ ions for the binding of some drugs".
Measuring magnesium in biological samples
By radioactive isotopes
The use of radioactive tracer elements in ion uptake assays allows the calculation of km, Ki and Vmax and determines the initial change in the ion content of the cells. 28Mg decays by the emission of a high energy beta or gamma particle, which can be measured using a scintillation counter. However, the radioactive half-life of 28Mg, the most stable of the radioactive magnesium isotopes, is only 21 hours. This severely restricts the experiments involving the nuclide. Additionally, since 1990 no facility has routinely produced 28Mg and the price per mCi is now predicted to be approximately US$30,000. The chemical nature of Mg2+ is such that it is closely approximated by few other cations. However, Co2+, Mn2+ and Ni2+ have been used successfully to mimic the properties of Mg2+ in some enzyme reactions, and radioactive forms of these elements have been employed successfully in cation transport studies. The difficulty of using metal ion replacement in the study of enzyme function is that the relationship between the enzyme activities with the replacement ion compared to the original is very difficult to ascertain.
By fluorescent indicators
A number of chelators of divalent cations have different fluorescence spectra in the bound and unbound states. Chelators for Ca2+ are well established, have high affinity for the cation, and low interference from other ions. Mg2+ chelators lag behind and the major fluorescence dye for Mg2+ (mag-fura 2) actually has a higher affinity for Ca2+. This limits the application of this dye to cell types where the resting level of Ca2+ is < 1 μM and does not vary with the experimental conditions under which Mg2+ is to be measured. Recently, Otten et al. (2001) have described work into a new class of compounds that may prove more useful, having significantly better binding affinities for Mg2+. The use of the fluorescent dyes is limited to measuring the free Mg2+. If the ion concentration is buffered by the cell by chelation or removal to subcellular compartments, the measured rate of uptake will only give minimum values of km and Vmax.
First, ion-specific microelectrodes can be used to measure the internal free ion concentration of cells and organelles. The major advantages are that readings can be made from cells over relatively long periods of time, and that unlike dyes very little extra ion buffering capacity is added to the cells.
Second, the technique of two-electrode voltage-clamp allows the direct measurement of the ion flux across the membrane of a cell. The membrane is held at an electric potential and the responding current is measured. All ions passing across the membrane contribute to the measured current.
Third, the technique of patch-clamp which uses isolated sections of natural or artificial membrane in much the same manner as voltage-clamp but without the secondary effects of a cellular system. Under ideal conditions the conductance of individual channels can be quantified. This methodology gives the most direct measurement of the action of ion channels.
By absorption spectrography
Flame atomic absorption spectroscopy (AAS) determines the total magnesium content of a biological sample. This method is destructive; biological samples must be broken down in concentrated acids to avoid clogging the fine nebulising apparatus. Beyond this the only limitation is that samples need to be in a volume of approximately 2 mL and at a concentration range of 0.1 – 0.4 µmol/L for optimum accuracy. As this technique cannot distinguish between Mg2+ already present in the cell and that taken up during the experiment only content not uptake can be quantified.
Inductively coupled plasma (ICP) using either the mass spectrometry (MS) or atomic emission spectroscopy (AES) modifications also allows the determination of the total ion content of biological samples. These techniques are more sensitive than flame AAS and are capable of measuring the quantities of multiple ions simultaneously. However, they are also significantly more expensive.
- Main article: Magnesium transport
The chemical and biochemical properties of Mg2+ present the cellular system with a significant challenge when transporting the ion across biological membranes. The dogma of ion transport states that the transporter recognises the ion then progressively removes the water of hydration, removing most or all of the water at a selective pore before releasing the ion on the far side of the membrane. Due to the properties of Mg2+, large volume change from hydrated to bare ion, high energy of hydration and very low rate of ligand exchange in the inner coordination sphere, these steps are probably more difficult than for most other ions. To date, only the ZntA protein of Paramecium has been shown to be a Mg2+ channel. The mechanisms of Mg2+ transport by the remaining proteins are beginning to be uncovered with the first three dimensional structure of a Mg2+ transport complex being solved in 2004.
The hydration shell of the Mg2+ ion has a very tightly bound inner shell of six water molecules and a relatively tightly bound second shell containing 12 – 14 water molecules (Markham et al., 2002). Thus recognition of the Mg2+ ion probably requires some mechanism to interact initially with the hydration shell of Mg2+, followed by a direct recognition/binding of the ion to the protein. Due to the strength of the inner sphere complexation between Mg2+ and any ligand, multiple simultaneous interactions with the transport protein at this level might significantly retard the ion in the transport pore. Hence, it is possible that much of the hydration water is retained during transport, allowing the weaker (but still specific) outer sphere coordination.
In spite of the mechanistic difficulty, Mg2+ must be transported across membranes, and a large number of Mg2+ fluxes across membranes from a variety of systems have been described. However, only a small selection of Mg2+ transporters have been characterised at the molecular level.
Effects in flotation therapy
It has recently been discovered that there is a secondary effect which is important in flotation therapy. Magnesium is absorbed through the skin due to natural molecular diffusion. This tends to correct magnesium deficiency. Magnesium is absorbed from the diet but in many areas of the world, over-cropping without adequate replacement of magnesium makes the normal diet low in magnesium.
- Magnesium Deficiency
- The Magnesium Website- Includes full text papers and textbook chapters by leading magnesium authorities Mildred Seelig, Jean Durlach, Burton M. Altura and Bella T. Altura. Links to over 300 articles discussing magnesium and magnesium deficiency.
- Dietary Reference Intake
- Healing Thresholds - description of research studies regarding supplementation with magnesium and other therapies for autism
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